Posttraumatic stress disorder (PTSD) affects 25% of those exposed to combat trauma. The heterogeneity in illness response to environmental factors can be attributed to genetic differences. Different individuals can experience the same trauma exposure and develop, or not develop, PTSD. This is consistent with the hypothesis that genetic vulnerability may confer risk for the disorder. Imaging genetics leverages the strengths of both neuroimaging and genetic studies, visualizing the brain activation patterns in the context of genetic background. Imaging as an intermediate phenotype can clarify the functional link between gene and disease phenotype. Given the known importance of both genetics and environment in brain function, and the role of neuroimaging in revealing brain dysfunction, the synergy of integrating genetics with brain imaging carries clear advantages: (i) the function of the genes of interest can be revealed in neuroimaging data, an intermediate phenotype which has relevance to many diseases; (ii) the unwanted variation in imaging studies can be reduced through controlling for genetic background; (iii) neuroimaging may identify dimensions of disease that are more closely related to susceptibility genes than are current clinical categorizations; (iv) gene discovery or the identification of new genes related to illness that would not be discovered by traditional candidate gene approaches. In this proposal, we plan to leverage the substantial investment of the Mid-Atlantic Mental Illness Education and Clinical Center in acquiring a large database of OEF/OIF veterans to investigate the influence of genes on the development of PTSD using neuroimaging phenotypes. This proposal reflects a collaboration of MIRECC clinicians, neuroimaging scientists, and psychiatric geneticists. Broadly, our three specific aims integrate advanced methods in brain imaging and human genotyping to identify new genes associated with PTSD and understand the role these genes play in brain function. Our first aim is to perform functional MRI studies on OEF/OIF veterans with PTSD (n=80) and trauma exposed controls (n=80) in a working memory task and emotion processing task to identify brain regions of differential activation. Our second aim is to assay a targeted list of five candidate genes based on biological plausibility in working memory and emotion processing. Our third aim is to analyze the genotype information from Aim 2 and brain activation information from Aim 1 to study the interaction of genotype, brain activation, and PTSD severity in dorsal frontoparietal regions and ventral frontolimbic regions. In this manner an imaging-genetics approach is expected to help identify genes associated with PTSD. PUBLIC HEALTH RELEVANCE: The mental health, social, and occupational impact of posttraumatic stress disorder (PTSD) on OEF/OIF veterans has received a great deal of attention at all levels of public discourse espically in mental health policy and delivery. PTSD affects 25% of those exposed to combat trauma. This suggests that differences in response to trauma exposure can be attributed to genetic differences. Understanding the effects of genes on brain function, behavior, and disease expression of PTSD are crucial to developing effective management and treatment.